Abstract
Neurodevelopment is achieved through a combination of tightly regulated processes, including neuronal migration and dendrites ramification. While the former takes place during the embryonic period, the latter occurs mainly during the postnatal period, and allows for neuronal wiring to take place. Alterations of those mechanisms can lead to a wide range of neurodevelopmental disorders such as autism and schizophrenia which are associated with sociability, memory and cognitive deficits. The serotonin 5-HT6 receptor (5-HT6R) is a Gs protein coupled receptor that holds special promise as a target for the treatment of the cognitive deficits associated with neurodevelopmental disorders [1]. However, the mechanisms underlying its impact upon neurodevelopment and cognition remain only partially characterized, mainly because of the absence of specific antibodies allowing to work in vivo, on the endogenous receptor.To address this issue we used a genetically modified « knock-in » mouse model expressing the 5-HT6R fused to a green fluorescent protein. We systematically explored the 5-HT6R expression pattern in several brain areas at four different developmental stages: embryonic (embryonic days E15-E17), postnatal (postnatal days P1-P10), adolescent (postnatal day P30) and adult (postnatal day P60) stages.Here, we show that the 5-HT6R is expressed as early as E15, in a wide variety of areas related to higher cognitive functions including the striatum, the hippocampus and the cortex. In all structures examined, the 5-HT6R is mostly expressed in projection neurons (about 94% of 5-HT6R-positive cells are projection neurons) and, to a lesser extent, in interneurons (1% of 5-HT6R-positive cells) and astrocytes (5% of 5-HT6R-positive cells). In embryonic, adolescent and adult mice, the 5-HT6R is detected almost exclusively in the primary cilium, an organelle extending from the soma of almost every cell type in the organism and thought to have important roles in cell signalling. Intriguingly, in post-natal mice (between P1 and P10), the 5-HT6R subcellular localization changes: the receptor becomes detectable in the somatic compartment of neurons, suggesting peculiar signalling abilities and thus a specific role of the receptor during the postnatal period, in which neuronal wiring takes place.To test the influence of the postnatal somatic 5-HT6R in neuronal wiring and the development of cognition in vivo, we inhibited the activity of the receptor using a specific inverse agonist (SB271046) during the postnatal period, between P1 and P10. We then performed a battery of behavioural tests on these treated mice, either at the adolescent (middle term) or adult stage (long term). Our preliminary results obtained with the Crawley’s sociability test indicate that the treated mice display an impaired sociability in the middle and long term. Other tests to investigate memory deficits (novel object recognition test) and anxiety (elevated plus maze) show no specific impairments. Thus, our data highlight an important role of the 5-HT6R in the development of specific behaviours such as social behaviour. Our future work will focus on the impact of the early life inhibition of the 5-HT6R on neuronal architecture and morphology in vivo, a feature that could correlate with the cognitive impairments encountered in neurodevelopmental disorders.Reference [1] Dayer, A.G., Jacobshagen, M., Chaumont-Dubel, S., Marin, P., 2015. 5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits. ACS Chem. Neurosci. 6, 951–960